Enantiomers of the n-(2-amino-5-fluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, as well as of the di- and trifluoro derivatives for the treatment of cardiovascular diseases

Abstract

The present application relates to novel 6-hydrogen-substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.

1 . Compound having the systematic name ent-N-(2-amino-5-fluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         2 . Compound having the systematic name ent-N-(2-amino-5-fluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         3 . Compound having the systematic name ent-N-(2-amino-4,4-difluoro-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         4 . Compound having the systematic name ent-N-(2-amino-4,4-difluoro-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         5 . Compound having the systematic name ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         6 . Compound having the systematic name ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         7 . Compound having the systematic name ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2-methyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         8 . Process for preparing the compound of  claim 1 , comprising:
 [A] reacting a compound of the formula (I)   
       
         
           
           
               
               
           
         
         in which 
         R 1  represents hydrogen or chlorine, 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (II) 
       
       
         
           
           
               
               
           
         
         in which 
         R 1  represents hydrogen or chlorine, 
         and subsequently reacting the carboxylic acid of the formula (II) in an inert solvent under amide coupling conditions with an amine selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         to give compounds of the formula (IV) 
       
       
         
           
           
               
               
           
         
         in which 
         R 1  represents hydrogen or chlorine, 
         and 
         R 2  represents (IV-A), (IV-B) or (IV-C) 
       
       
         
           
           
               
               
           
         
         where * represents the point of attachment to the nitrogen atom, 
         and, if R 1  represents chlorine, 
         hydrogenating these in an inert solvent in the presence of a suitable transition metal catalyst, 
         and optionally converting the resulting compounds with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof. 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . Medicament comprising the compound as defined in  claim 1  in combination with an inert, nontoxic, pharmaceutically suitable excipient. 
     
     
         12 . Medicament comprising the compound as defined in  claim 1  in combination with a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers. 
     
     
         13 . (canceled) 
     
     
         14 . Method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of at least one compound as defined in  claim 1  to a human or animal in need thereof. 
     
     
         15 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the medicament of  claim 11  to a human or animal in need thereof. 
     
     
         16 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the medicament of  claim 12  to a human or animal in need thereof.